PTSD: The “Golden Week”.

In cases of myocardial infarction time is of the essence. If a patient is brought to the ER within an hour of the heart attack, chances are excellent that damage to the heart can be largely avoided. This is referred to as “the golden hour”. Other clinical events have their “golden” time period (for instance, 4 hours for stroke), although we are mostly ignorant as to the why and the how of these windows of opportunity.

One such event is the psychological consequence of trauma. Soldiers returning from war break out in cold sweat and panic reaction in response to the sound of a car backfire, or even the innocuous pop of uncorking a bottle of champagne. Clinical psychologists have tried, with varying degrees of success, to treat these patients with a procedure called ’extinction’.

To understand ‘extinction’, think of the boy who cried wolf. The first couple of times he raised alarm among the townspeople. But with each additional cry of ‘wolf’ without an actual wolf materializing, the townspeople learned to ignore the cry. Or think of the poor Pavlovian dog which learned to interpret bell ringing as a cue for food. After each ring the dog started salivating in anticipation of a scrumptious bone. But if we tried to fool the dog by ringing the bell without the reward of a bone, eventually he would ignore the cue, as if knowing that we are only teasing him. You can fool all the dogs some of the time, but you can’t fool them all the time.

So it stands to reason that extinction therapy should work with PTSD patients. Expose a soldier with PTSD to repeated sounds of faux explosions, and eventually he will grow inured to the cue. Indeed, this treatment is quite successful. But in many cases, full extinction is not attained; the patient may relapse and react with fear to old cues even years after apparent extinction. Conclusion: memory of the fear reaction has not been erased. It is still lurking in the recesses of brain, waiting patiently to resurface and strike panic.

Of Mice and Men

One can strike fear in the hearts (and minds) of mice by exposing them to a mild electric shock every time they approach a dish of food. Very soon they learn to avoid that dish. This is called in Psychology “conditioned response”. And in a classic extinction procedure, if the food is then presented without the attending shock, the mice will eventually “forget” the unpleasant shock and approach the food as if nothing had happened. Are the mice dumb? Maybe, but I doubt it. What really happened is that with the passage of time the fear response was extinguished. Time, as the saying goes, is the best healer. Well, this immediately begs the question: how much time?

A series of experiments showed that if the extinction experiment is done within one week of the conditioned response, extinction is accomplished more easily and permanently. After that, results are more variable. What this implies is that there is something special about the fear-inducing memory during this time period that renders it more susceptible to permanent extinction. Is this relevant to our traumatized soldier or traffic accident victim? To understand this qualitative difference between one week and longer than a week, and maybe take therapeutic advantage of it, we need to understand the underlying mechanism.

In a Report in the 19 Nov 2010 Science (published online 28 Oct), Clem and Huganir shed light on the neural basis of this fear erasure. Using a combination of electrophysiology and behavioral training in mice, the team observed that fear conditioning (the process by which the animals learn to be afraid of a given stimulus) increases synaptic transmission by calcium-permeable glutamate receptors known as AMPARs into the amygdala — the part of the brain that controls emotional responses. This effect lasted for about a week, during which the fearful memories could be erased if the animals were then trained to reduce the conditioned fear responses. Postmortem brain slices confirmed that the synaptic changes acquired during fear conditioning were actually reversed in mice that had undergone fear extinction training during this week-long window of opportunity. These results reveal a molecular mechanism for fear erasure and the relative instability of recent memory.

It is rare that scientists can demonstrate such close concordance between behavior and neurobiology. We think of behavior as inherently complex, not amenable to simple 1:1 relationships. Such a result is rare, and highly satisfying. It is also a demonstration that at the end of the day behavior is rooted in simple neurobiological events in the brain –something that intuitively many of us find hard to accept.

But beyond the sheer scientific satisfaction –think of the clinical implication. The military should make it a standard operating procedure to subject soldiers in combat to close monitoring and immediate extinction treatment when indicated. ER doctors should become aware of PTSD and its harmful long lasting effects in patients brought in after heart attacks, traffic accidents, or even ‘run-of-the-mill’ mugging. A short behavioral extinction treatment, or even an amnestic (memory-erasing) drug could avoid future debilitating suffering and save lots of money as well.

Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.

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